Chronic lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are leading causes of mortality and morbidity worldwide that impose major economic and societal burdens. In the past decades, considerable progress has been made in identifying and studying disease-specific genes and proteins to understand the molecular mechanisms of underlying disease processes. Yet there is a large disconnect between this biochemical basis of disease and the reality of how these diseases develop and manifest themselves. Scientists and caregivers have long recognized that many chronic lung diseases are associated with abnormal changes in the structure and mechanics of the lung. The current focus of pulmonary research on genetics and biochemistry, however, largely ignores this undeniable physical nature of disease, rendering our fundamental understanding incomplete. The greatest challenge in resolving this lack of knowledge has been in the inability of conventional experimental approaches to recapitulate complex pathological mechanical changes in the lung during disease development and progression. To address this critical barrier, we propose to develop a new paradigm of in vitro studies for pulmonary research by leveraging unique capabilities of microengineering technologies to create new types of surrogate models that reconstitute the structural, functional, and mechanical complexity of chronic lung diseases. Specifically, using asthma as a representative disorder, this proposal aims to develop novel bioengineering approaches based on the synergistic integration of microengineered culture of patient-derived cells with dynamic self-assembly, hydrogel engineering, and multiphase microfluidics to build mechanically active human disease models. We will use a microengineered model of asthma to study whether and how aberrant changes in tissue architecture and local mechanical microenvironment influence airway inflammation and remodeling, which are the defining pathological features of asthma and many other chronic lung diseases. Of particular interest is in examining biomechanical disease processes in the small airways of asthmatic lungs to address the current lack of knowledge regarding inflammatory and remodeling responses in the distal lung during the progression of chronic asthma. This research will address critical technical barriers to progress in pulmonary medicine, mechanobiology and many other related areas, and provide new insights into important biological questions, which may contribute to the identification of new therapeutic targets and intervention strategies.